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Systemic blood pressure (BP) may oscillate for homeostatic needs (equilibrium by constancy) or just as shifts in other intrinsic and extrinsic variables known as allostatic changes. This transitory pressure often rises alerts physicians to out-of-control hypertension or even hypertensive crisis. There is a very complex theory underlying these stochastic phenomena, which physicists and mathematicians translate into a single word: chaos. These changes happen according to a stochastic probabilistic pattern that presumes chaotic but somewhat predictable and nonlinear modeling of BP-related dynamics as a mathematical approach. Based on the chaos theory, small changes at the initial BP (baseline overtime) values could disturb the homeostasis leading to extreme BP chaotic shifts. These almost insignificant oscillations may also affect other variables and systems, leading to the misdiagnosis of hypertension, "out-of-control" BP levels, and resistant hypertension (RHT). Thus, these unpredictable and transient increases in BP values may be improperly diagnosed as the white coat and masked or resistant hypertension. Indeed, the interference of the chaos in any phenotype of (true or false) hard to control BP is not considered in clinical settings. This review provides some basic concepts on chaos theory and BP regulation. Besides pseudoresistant hypertension (lack of adherence, circadian variations, and others (white-coat, masked, early morning effects or hypertension), chaotic changes can be responsible for out-of-control hypertension., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

This study aimed to evaluate the effects of glycated hemoglobin (HbA 1c ) on flow-mediated dilation, intima-media thickness, pulse wave velocity, and left ventricular mass index in patients with resistant hypertension (RHTN) comparing RHTN-controlled diabetes mellitus and RHTN-uncontrolled type 2 diabetes mellitus. Two groups were formed: HbA 1c <7.0% (RHTN-controlled diabetes mellitus: n = 98) and HbA 1c ≥7.0% (RHTN-uncontrolled diabetes mellitus: n = 122). Intima-media thickness and flow-mediated dilation were measured by high-resolution ultrasound, left ventricular mass index by echocardiography, and arterial stiffness by carotid-femoral pulse wave velocity. No differences in blood pressure levels were found between the groups but body mass index was higher in patients with RHTN-uncontrolled diabetes mellitus. Endothelial dysfunction and arterial stiffness were worse in patients with RHTN-uncontrolled diabetes mellitus. Intima-media thickness and left ventricular mass index measurements were similar between the groups. After adjustments, multiple linear regression analyses showed that HbA 1c was an independent predictor of flow-mediated dilation and pulse wave velocity in all patients with RHTN. In conclusion, HbA 1c may predict the grade of arterial stiffness and endothelial dysfunction in patients with RHTN, and superimposed uncontrolled diabetes mellitus implicates further impairment of vascular function., (©2018 Wiley Periodicals, Inc.)

The authors previously demonstrated that acute administration of sildenafil-a phosphodiesterase 5 (PDE5) inhibitor-improves hemodynamic parameters in patients with resistant hypertensive (RH), but its effect on ambulatory blood pressure monitoring (ABPM) is unknown. This interventional, nonrandomized, single-blinded, placebo-controlled, crossover trial included 26 patients with RH. A dose of sildenafil (187.5mg) was given, and after a washout period of 14 days the patients received a single oral dose of placebo and the protocol was repeated. The patients underwent 24-hour ABPM recordings the day before and immediately after the protocols. The reduction of systolic (-8.8±1.4 vs 1.3±1.2 mm Hg, P=.02), diastolic (-5.3±3.3 vs 1.8±1.1 mm Hg, P=.03), and mean (-7.9±3.6 vs 0.8±0.9 mm Hg, P=.01) 24-hour BP were found after the use of sildenafil compared with placebo. Improvement in daytime BP levels was also observed (systolic -6.0±4.7 vs 4.4±1.5 mm Hg [P=.02] and mean -4.8±3.9 vs 3.5±1.4 mm Hg [P=.02] for sildenafil vs placebo, respectively). Considering its antihypertensive effect, sildenafil may represent a therapeutic option for RH treatment., (©2016 Wiley Periodicals, Inc.)

Resistant hypertension (RH) is associated with organ damage and cardiovascular risk. Evidence suggests the involvement of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in hypertension and in cardiovascular remodeling. The aim of this study was to assess the levels of MMP-2 and TIMP-2 in RH and its relation with organ damage, including arterial stiffness and cardiac hypertrophy. MMP-2 and TIMP-2 levels were compared among 19 patients with normotension (NT), 116 with nonresistant hypertension (HTN) and 116 patients with resistant HTN (RH). MMP-2 levels showed no differences among NT, HTN, and RH groups, while TIMP-2 levels were higher in RH compared with HTN and NT groups (90.0 [76.1-107.3] vs 70.1 [57.7-88.3] vs 54.7 [40.9-58.1] ng/mL, P<.01), respectively. MMP-2/TIMP-2 ratio was reduced in the RH group compared with the HTN and NT groups (2.7 [1.9-3.4] vs 3.3 [2.6-4.2] vs 4.9 [4.5-5.3], P<.01), respectively. No associations were found between MMP-2 levels, TIMP-2, and MMP-2/TIMP-2 ratio with cardiac hypertrophy and arterial stiffness in the RH and HTN groups. Finally, in a regression analysis, reduced MMP-2/TIMP-2 ratio and increased TIMP-2 levels were independently associated with RH. The present findings provide evidence that TIMP-2 is associated with RH and might be a possible biomarker for screening RH patients., (©2016 Wiley Periodicals, Inc.)

Resistant hypertension (RH) is a multifactorial disease, frequently associated with obesity and characterized by blood pressure above goal (140/90 mm Hg) despite the concurrent use of ≥3 antihypertensive drugs of different classes. The mechanisms of obesity-related hypertension include, among others, aldosterone excess and inflammatory adipokines, which have demonstrated a significant role in the pathogenesis of metabolic syndrome and RH. This review aims to summarize recent studies on the role of the adipokines leptin, resistin, and adiponectin in the pathophysiology of RH and target-organ damage associated with this condition. The deregulation of adipokine levels has been associated with clinical characteristics frequently recognized in RH such as diabetes, hyperactivity of sympathetic and renin-angiotensin-aldosterone systems, and vascular and renal damage. Strategies to regulate adipokines may be promising for the management of RH and some clinical implications must be considered when managing controlled and uncontrolled patients with RH., (© 2014 Wiley Periodicals, Inc.)

Aldosterone excess or "escape" can occur after treatment with medications that block the renin-angiotensin-aldosterone system or in undiagnosed primary aldosteronism. Spironolactone is thought to be an important addition to resistant hypertension (RH) treatment. In this study, resistant (RH) and controlled (CH) hypertensives and normotensive patients were submitted to echocardiography, flow-mediated vasodilation, carotid intima-media wall thickness studies, renin plasma activity, and aldosterone plasma levels and plasma and urinary sodium and potassium concentrations at baseline (pre-spironolactone phase). Subsequently, for only RH and CH groups, 25 mg/d spironolactone was added to preexisting treatments over 6 months. Afterwards, these parameters were reassessed (post-spironolactone phase). The RH and CH groups achieved reductions in blood pressure (P<.001), decreases in left ventricular hypertrophy (P<.001), improved diastolic function (Kappa index RH: 0.219 and Kappa index CH: 0.392) and increases in aldosterone concentrations (P<.05). The RH group attained improved endothelium-dependent (P<.001) and independent (P=.007) function. Optimized RH treatment with spironolactone reduces blood pressure and improves endothelial and diastolic function and left ventricular hypertrophy despite the presence of aldosterone excess or escape.

Intensive monitoring of adherence in patients with uncontrolled hypertension was evaluated over a 6-month period. After that period, only patients well characterized as having resistant hypertension were followed for 12 months. The goal of this study was to evaluate whether adherence to a drug regimen helps to identify patients with resistant hypertension. Forty-four hypertensive patients resistant to a 3-drug regimen (average blood pressure [BP] mm Hg, mean +/- standard deviation) were studied prospectively. Each patient was followed for a 12-month period. Adherence to treatment was evaluated through self-report, applying Morisky's questionnaire and the pill count method. Ambulatory BP monitoring and office BP measures were performed. By pill count, 63.6% of the patients were adherent to treatment at the start of the survey and 94% at the end, although 59% of the patients still did not reach normal BP levels. We found that non-adherence was not associated with resistance to antihypertensive treatment. Therefore, after investigation, we concluded that patients who presented with uncontrolled arterial BP may be truly resistant hypertensive to treatment.

Veins and arteries have active endothelium, producing vasoactive substances like nitric oxide. The aim of this study was to evaluate whether hypertensive patients exhibit venous endothelial dysfunction and to determine the relationship between endothelial-dependent and endothelial-independent vasodilation responses in venous and arterial systems. Sixteen unmedicated patients with stage I and II hypertension and without other risk factors and 15 matched normotensive volunteers had venous and arterial endothelial function evaluated with the dorsal hand vein technique and brachial artery ultrasonography. Hypertensive patients had a marked reduction of maximum dilation to acetylcholine (54.9% +/- 21.6%) compared with normotensive controls (85.2% +/- 27.0%). The flow-mediated dilation responses were reduced in hypertensive patients compared with controls (6.6% +/- 3.3%vs 12.4% +/- 2.6%, respectively). The responses to nitric oxide were similar in both groups, and the responses with the dorsal hand vein technique and flow-mediated dilation agreed in both groups. Hypertensive patients had an attenuated endothelial dependent response, indicating that endothelial dysfunction is also present in the venous system.

Renin-angiotensin-aldosterone system (RAAS) hyperactivity is implicated in the development of hypertension and progressive damage in target organs. Chronic inhibition of the RAAS or use of thiazide-type diuretics may trigger an aldoster-one escape. The aim of this study was to assess this phenomenon in hypertensive patients treated with thiazide-type diuretics (hydrochlorothiazide [HCTZ]) or single or double blockade of the RAAS (irbesartan [IRBE], quinapril [QUIN], and IRBE+QUIN). Blood pressure levels were obtained by 24-hour ambulatory blood pressure monitoring. Plasma renin activity and aldosterone levels were determined by immunoradiometric assay. Blood pressure level was normalized in the 4 treatment groups; the HCTZ and IRBE+QUIN groups showed an increased plasma aldosterone level after 12 weeks (9.1+/-2.2 to 14.1+/-1.4 and 6.9+/-1.9 to 12.9+/-2.3 ng/dL, respectively; P<.05), whereas plasma renin activity was increased only in the HCTZ group (0.9+/-0.2-1.7+/-0.2 ng/mL/h; P<.05). The increase in plasma aldosterone level after 12 weeks of HCTZ and IRBE+QUIN therapy suggests early aldosterone escape.

It is unclear whether single and combined pharmacologic inhibition of the renin-angiotensin-aldosterone system have similar effects on endothelial function and blood pressure (BP). The authors evaluated 63 hypertensive patients divided into 4 groups (hydrochlorothiazide 25 mg/d; irbesartan [IRBE] 150 mg/d; quinapril [QUIN] 20 mg/d; or IRBE 150 mg/d + QUIN 20 mg/d) and 25 healthy normotensive subjects (normal) followed for 12 weeks. Endothelium-dependent dysfunction measured as flow-mediated dilation at Weeks 0 and 12 were: normal, 11.5%±2.4% vs 13.5%±2.0%; hydrochlorothiazide, 7.3%±2.0% vs 12.8%±3.1%; QUIN, 7.2%±2.8% vs 13.2%±2.1%; IRBE, 7.1%±2.8% vs 13.0%±2.9%; and IRBE + QUIN, 7.5%±1.9% vs 12.8%±3.0%. Nitroglycerin-mediated responses were: normal, 26.0%±1.9% vs 24.0%±2.5%; hydrochlorothiazide, 17.0%±2.2% vs 18.3%±2.6%; QUIN, 17.8%±3.2% vs 23.4%±3.0%; IRBE, 16.8%±3.6% vs 24.7%±2.0%; and IRBE + QUIN, 17.3%±3.0% vs 25.1%±2.5%. Antihypertensive therapy restored BP to normal and improved the endothelium-dependent and -independent dysfunction after renin-angiotensin-aldosterone system blockade. In a further finding, the combined effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade was not superior to the action of either of these treatments separately.

It is unclear whether single and combined pharmacologic inhibition of the renin-angiotensin-aldosterone system have similar effects on endothelial function and blood pressure (BP). The authors evaluated 63 hypertensive patients divided into 4 groups (hydrochlorothiazide 25 mg/d; irbesartan [IRBE] 150 mg/d; quinapril [QUIN] 20 mg/d; or IRBE 150 mg/d + QUIN 20 mg/d) and 25 healthy normotensive subjects (normal) followed for 12 weeks. Endothelium-dependent dysfunction measured as flow-mediated dilation at Weeks 0 and 12 were: normal, 11.5%+/-2.4% vs 13.5%+/-2.0%; hydrochlorothiazide, 7.3%+/-2.0% vs 12.8%+/-3.1%; QUIN, 7.2%+/-2.8% vs 13.2%+/-2.1%; IRBE, 7.1%+/-2.8% vs 13.0%+/-2.9%; and IRBE + QUIN, 7.5%+/-1.9% vs 12.8%+/-3.0%. Nitroglycerin-mediated responses were: normal, 26.0%+/-1.9% vs 24.0%+/-2.5%; hydrochlorothiazide, 17.0%+/-2.2% vs 18.3%+/-2.6%; QUIN, 17.8%+/-3.2% vs 23.4%+/-3.0%; IRBE, 16.8%+/-3.6% vs 24.7%+/-2.0%; and IRBE + QUIN, 17.3%+/-3.0% vs 25.1%+/-2.5%. Antihypertensive therapy restored BP to normal and improved the endothelium-dependent and -independent dysfunction after renin-angiotensin-aldosterone system blockade. In a further finding, the combined effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade was not superior to the action of either of these treatments separately.

Nicotine replacement therapy appears to be safe when used by healthy patients to aid in smoking cessation; however, the immediate acute effects of nicotine replacement therapy on the circadian rhythm of blood pressure (BP) and endothelial function in heavy smokers are not well understood. Twenty-six heavy smokers were requested to stop smoking for 48 hours. BP and heart rate were recorded over 48 hours by ambulatory BP monitoring, with beat-to-beat changes being monitored for the first 10 hours by a noninvasive finger device. The reactivity of the brachial artery was evaluated using flow-mediated dilation immediately after smoking cessation, before the application of a 21-mg nicotine patch or placebo patch, and 24 hours after patch placement. Transdermal nicotine caused a mild but significant elevation in BP in the early morning in 21 of 26 volunteers. The decrease in nocturnal BP was attenuated in patients with the nicotine patch compared with the placebo patch; this was associated with impaired endothelium-dependent vasodilation.